Ureins derived from α, ω-diamino acids and process for their preparation

ABSTRACT

Ureins are obtained by reaction, in basic medium, between an N ω -(aryloxycarbonyl)diamino acid and a compound containing a free amino group. The chirality of the compounds is outstandingly well preserved.

This is Division of Application Ser. No. 08/985,658 filed Jun. 17, 1997now U.S. Pat. No. 6,060,586 which in turn is a continuation of Ser. No.08/257,292 filed Jun. 9, 1994, now abandoned. The entire disclosure ofthe prior application is hereby incorporated by reference herein in itsentirety.

The present invention relates to new ureins derived from α, ω-diaminoacids and to a new process for the preparation of such compounds.

Ureins derived from diamino acids can conventionally be prepared bycarbamoylation by means of a cyanate or of an isocyanate. This knownprocedure does not, however, appear entirely satisfactory, mainly due toinsufficient specificity of these reactants for the amino functionalgroup to be carbamoylated and due to the sometimes significantracemization which such a treatment can cause.

The invention overcomes the disadvantages of the conventional processesby providing a new, particularly outstanding, process which makes itpossible to obtain the desired product with an improved chemical yieldwhile retaining outstandingly well the chiral purity of the compoundsused.

The invention consequently relates to a process for the preparation ofureins derived from an α,ω-diamino acid, according to which a compoundcontaining a free amino group is reacted, in basic medium, with adiamino acid derivative containing an N^(ω)-aryloxycarbonyl group.

Urein is understood to denote any compound whose molecular structurecontains the structure —NH—CO—NH—.

Amino acid is understood to denote, for the purposes of the presentinvention, any compound comprising at least one amino group and at leastone carboxyl group. By extension, the term “amino acid” is alsounderstood to encompass hereinbelow any amino acid in which certainother groups are optionally bonded to organic groups such as protectivegroups. In particular, α,ω-diamino acid is understood to denote anyamino acid comprising at least one amino group and at least one carboxylgroup bonded to the same carbon atom of the molecule and additionallycomprising at least one other amino group bonded to another carbon atom.It most often concerns a compound of general formula

in which A represents a bivalent group consisting of a carbon chaincontaining 1 to 8 carbon atoms, which chain is optionally substituted byone or a number of groups chosen from C₁-C₃ alkyl groups and functionalgroups comprising at least one oxygen or sulphur atom such as acarboxyl, acyl, hydroxyl, alkoxy or mercapto group, without the totalnumber of carbon atoms in the group A being greater than 15. A ispreferably a polymethylene group comprising from 2 to 5 carbon atoms.Mention may be made, as examples of α,ω-diamino acids, of especially2,3-diaminopropanoic acid, 2,4-diaminobutanoic acid, ornithine, lysine,homolysine, 5-hydroxylysine, 6-methyl-lysine and 2,6-diaminopimelicacid.

Diamino acid derivative containing an N^(ω)-aryloxycarbonyl group, alsosubsequently known as N^(ω)-(aryloxycarbonyl)diamino acid, is understoodto denote any α,ω-diamino acid derivative in which an aryloxycarbonylgroup of formula R—O—CO—, R symbolizing an aryl group, is bonded to thenitrogen atom of the ω-amino group of the diamino acid.

In the process according to the invention, the use of a diamino acidderivative containing an N^(ω)-aryl-oxycarbonyl group is critical. Infact, it is apparent, surprisingly, that the aryloxycarbonyl groupbonded to the ω-amino group of the amino acid leads, in the presence ofa compound containing a free amino group, to the formation of a urein bysubstitution of the aryloxy fragment of the said aryloxycarbonyl groupby the free amino group of the said compound.

The N^(ω)-aryloxycarbonyl derivative of the diamino acid used generallycontains, as aryloxycarbonyl group, a group comprising from 7 to 15carbon atoms. This aryloxycarbonyl group is most often aphenyloxycarbonyl or naphthyloxycarbonyl group optionally substituted byat least one group chosen from alkyl groups comprising from 1 to 4carbon atoms and the nitro group. Mention may be made, as examples ofaryloxycarbonyl groups which can be used in the process according to theinvention, of the phenyloxycarbonyl, tolyloxycarbonyl, xylyloxycarbonyl,mesitylyloxycarbonyl, ethylphenyloxycarbonyl, diethyl-phenyloxycarbonyl,propylphenyloxycarbonyl, isopropyl-phenyloxycarbonyl,naphthyloxycarbonyl and nitrophenyl-oxycarbonyl groups. Thearyloxycarbonyl group is preferably a phenyloxycarbonyl orp-tolyloxycarbonyl group. Good results have been obtained in the processaccording to the invention with the N^(ω)-phenyloxycarbonyl derivativeof the diamino acid.

An N^(ω)-aryloxycarbonyl derivative of any α,ω-diamino acid can be usedin the process according to the invention.

The N^(ω)- (aryloxycarbonyl)diamino acid is a product which isinexpensive and readily accessible. It can be prepared conventionally byresorting to well known selective acylation techniques, for example viathe copper complex according to a procedure similar to that described inparticular in “Methoden Der Organischen Chemie” (Houben-Weyl), 1974,Volume XV/1, p. 472, concerning N^(ε)-benzyloxycarbonyl-L-lysine. As theα-amino functional group is complexed by the copper ion, thearyloxycarbonyl group can be selectively attached to the ω-aminofunctional group of the diamino acid by reaction with an arylchloroformate or an aryloxycarbonyloxysuccinimide.

The compound comprising a free amino group which reacts with theN^(ω)-(aryloxycarbonyl)diamino acid in the process according to theinvention is any compound of general formula R1R2NH in which R1 and R2represent, independently of one another, hydrogen atoms or alkyl,cycloalkyl or aralkyl radicals or in which R1 and R2 together form analicyclic radical. In this compound, the alkyl, cycloalkyl, aralkyl oralicyclic radicals can be substituted by one or a number of functionalgroups comprising at least one oxygen, sulphur or nitrogen atom, forexample by a carboxyl, hydroxyl, mercapto, indolyl or imidazolyl group.Compounds which can be used in the process according to the inventionare in particular ammonia, primary or secondary amines and the aminoacids as defined above. The process according to the invention isparticularly advantageous when the compound comprising a free aminogroup is an amino acid.

When the N^(ω)-(aryloxycarbonyl)diamino acid is a derivative of anα,ω-diamino acid in which the carbon chain of the group A consists of 1to 3 carbon atoms, the N^(ω)-(aryloxycarbonyl)diamino acid acts, in theprocess according to the invention, both as Nω-aryloxycarbonylderivative and, via its α-amino group, as compound containing a freeamino group. The result thereof, via an intramolecular reaction, is theformation of cyclic ureins of general formula

in which A represents a bivalent group consisting of an optionallysubstituted linear carbon chain formed from 1 to 3 carbon atoms.

In the process of the invention; by way of illustration,N^(β)-aryloxycarbonyl-2,3-diaminopropanoic acid forms2-oxoimidazolidinyl-4-carboxylic acid, N^(γ)-aryloxycarbonyl--2,4-diaminobutyric acid forms 2-oxohexahydropyrimidinyl-4-carboxylic acidand N⁶⁷ - (aryloxycarbonyl)ornithine forms2-oxohexahydro-1,3-diazepinyl-4-carboxylic acid.

When the N^(ω)-(aryloxycarbonyl)diamino acid is a derivative of anα,ω-diamino acid in which the carbon chain of the group A consists of atleast 4 carbon atoms, the N^(ω)- (aryloxycarbonyl)diamino acid isconverted, in the process according to the invention, into a non-cyclicurein of general formula

in which R1 and R2 have the same meaning as above and in which Arepresents a bivalent group consisting of an optionally substitutedlinear carbon chain formed from at least 4 carbon atoms. In the processof the invention, by way of illustration, homocitrulline is obtained byreaction between N^(ε)-(phenyloxycarbonyl)lysine and ammonia. When thecompound comprising a free amino group is an amino acid, anN^(ω)-(carboxyalkylcarbamoyl)-α,ω-diamino acid is obtained by theprocess according to the invention.

An N^(ω)-(aryloxycarbonyl)diamino acid incorporated in a peptide chaincan, without disadvantage, be used in the process according to theinvention. In particular, when the N^(ω)- (aryloxycarbonyl) diamino acidis a derivative of an α,ω-diamino acid in which the carbon chain of thegroup A consists of 1 to 3 carbon atoms and when this compoundconstitutes the N-terminal residue of a peptide chain, the processaccording to the invention makes it possible easily to obtain peptidesof general formula

in which A represents a bivalent group consisting of an optionallysubstituted linear carbon chain formed from 1 to 3 carbon atoms and inwhich NH—P represents any peptide chain bonded to the cyclic urein viaan amide bond.

The process according to the invention is carried out in a basic medium.

The process according to the invention is generally carried out in aliquid medium in which the N^(ω)-(aryloxycarbonyl)diamino acid and thecompound comprising a free amino group are at least partially solubleand preferably entirely soluble. Depending on the nature of thereactants, the medium can comprise water and/or an organic solvent.Organic solvents which are suitable in the process according to theinvention are lower alcohols such as in particular methanol, ethanol andisopropanol, tetrahydrofuran and dimethoxyethane. Media consisting ofwater and of a water-miscible organic solvent are preferred. Goodresults have been obtained in particular in a water/ethanol medium.

The basicity of the medium can be obtained by addition of a basiccompound to the medium, for example by addition of an inorganic basesuch as LiOH, NaOH or KOH or by addition of an organic base which isinert under the reaction conditions, such as a tertiary amine. Goodresults have, in particular, been obtained in the presence of LiOH or oftriethylamine. When the compound containing a free amino group is anamino acid containing free carboxyl functional groups, the basiccompound must be used in an amount sufficient to neutralize the carboxylfunctional groups.

In order to obtain cyclic ureins, the intra-molecular reactivity of theN^(ω)-(aryloxycarbonyl) diamino acid is such that it is possible,without problems, to add a compound containing a free amino group, suchas ammonia, to achieve the desired basicity of the medium, without thisappreciably affecting the yield of the reaction in cyclic urein.

In order to obtain non-cyclic ureins, when the α-amino group of theN^(ω)-(aryloxycarbonyl)diamino acid is free, it is necessary, in orderto avoid a condensation reaction of the N^(ω)-(aryloxycarbonyl)diaminoacid concurrent with the desired reaction with the compound containing afree amino group, to operate with an excess, with respect to thestoichiometric amount necessary, of the compound containing a free aminogroup which it is desired to react with theN^(ω)-(aryloxycarbonyl)diamino acid. Good results are obtained when thereaction is carried out with a molar ratio of the compound containing afree amino group to the N^(ω)- (aryloxycarbonyl) diamino acid which isat least equal to 3. The reaction is preferably Carried out with a ratioat least equal to 4. In principle, there is no upper limit to thisratio. In practice, however, it is generally pointless to carry out thereaction with a molar ratio of the compound containing a free aminogroup to the N^(ω)-(aryloxycarbonyl)diamino acid which is greater than100. The molar ratio most often does not exceed 10. When the compoundcontaining a free amino group is an amino acid or a peptide, the molarratio preferably does not exceed 7. When the compound containing a freeamino group has a sufficiently basic nature, it may prove to bepointless to add another basic compound to the medium.

The process according to the invention can be implemented in a wideconcentration range of the reactants in the liquid medium, in particularfor obtaining cyclic ureins. The N^(ω)-(aryloxycarbonyl)diamino acid isgenerally used at a concentration of 0.05 to 5 mol/l, preferably of 0.1to 1 mol/l.

The reaction can be carried out from room temperature to the boilingtemperature of the organic solvent. It is advantageously carried outfrom 30 to 80° C. A temperature of 40 to 60° C. is very particularlypreferred.

Under these conditions, the reaction time is generally less than 10hours. The reaction is most often complete after a time of 30 minutes to4 hours.

The process according to the invention appears particularly advantageousfor preparing ureins derived from α,ω-diamino acids. TheN^(ω)-aryloxycarbonyl derivative for the diamino acid used in theprocess according to the invention can be easily and cheaply preparedfrom the diamino acid. It can easily be isolated in the pure form. It isstable and can be stored for a long time without deteriorating. Theprocess according to the invention is particularly outstanding. It makesit possible to obtain the desired ureins with a very high yield. Itadditionally has very little effect on the chirality of the compoundsused. Moreover, the departure of the aryloxy fragment of thearyloxycarbonyl group only generates relatively inoffensive by-productsin the medium which do not disturb the synthesis. For example, when itconcerns the phenyloxycarbonyl group, only phenol is generated.Consequently, when the compounds used contain very labile groups, suchas certain protective groups, the by-products generated in the medium donot cause any damage to these compounds. Purification of the desiredproducts is markedly simpler than in the previous known processes.

The invention also relates to N^(ω)-carboxyalkyl-carbamoyl-α, ω-diaminoacids, ureins derived from an α,ω-diamino acid, of general formula

in which A represents a bivalent group consisting of a linear carbonchain formed from 4 to 8 carbon atoms, which chain is optionallysubstituted by one or a number of groups chosen from C₁-C₃ alkyl groupsand functional groups comprising at least one oxygen or sulphur atomsuch as a carboxyl, acyl, hydroxyl, alkoxy or mercapto group, and inwhich R3—NH represents an amino acid or a peptide. A is preferably apolymethylene group containing 4 or 5 carbon atoms. R3—NH is preferablyan amino acid and more preferentially an essential amino acid.

These new compounds constitute compounds with a structure similar tothat of dipeptides and can be used in particular in place of thecorresponding dipeptides, in particular as a source of essential aminoacids in parenteral human feeding or in animal feeding.

The invention also relates to the cyclic ureins of general formula

in which A represents a bivalent group consisting of a linear carbonchain formed from 1 to 3 carbon atoms, which chain is optionallysubstituted by one or a number of groups chosen from C₁-C₃ alkyl groupsand functional groups comprising at least -one oxygen or sulphur atomsuch as a carboxyl, acyl, hydroxyl, alkoxy or mercapto group, with theexception of 2-oxoimidazolidinyl-4-carboxylic acid and(LD)-2-oxohexahydropyrimidinyl-4-carboxylic acid. A preferablyrepresents a bivalent group consisting of an optionally substitutedcarbon chain consisting of 2 or 3 carbon atoms. In a particularlypreferred way, A represents a trimethylene group -(CH₂)₃-. In this case,the urein formed is 2-oxohexahydro-1,3-diazepinyl-4-carboxylic acid,easily obtained by the process according to the invention fromornithine.

Depending on whether the (D) or (L) enantiomer of the diamino acid isused in the process according to the invention, the (D) or (L)enantiomer of the corresponding cyclic urein is obtained in the chirallypure form.

These cyclic ureins can be used in particular as the N-terminal residueof certain biologically active peptides, such as the hormone TRH(Thyrotropin Releasing Hormone), by replacing the N-terminalpyroglutamyl group of this peptide.

Finally, the invention relates to peptides analogous to TRH, of generalformula

in which A is a bivalent group consisting of a linear carbon chainformed from 2 or 3 carbon atoms, which chain is optionally substitutedby one or a number of groups chosen from C₁-C₃ alkyl groups andfunctional groups comprising at least one oxygen or sulphur atom such asa carboxyl, acyl, hydroxyl, alkoxy or mercapto group. A is preferably apolymethylene group. The peptide in which A is a trimethylene group ispreferred. These peptides have an increased resistance to proteolyticdigestion while retaining a high biological activity.

The symbolic representations of the amino acids and of the peptidesadopted in the description and examples follow the IUPAC nomenclaturerecommendations generally adopted and described, for example, in“Nomenclature and Symbolism for Amino Acids and Peptides,Recommendations 1983”, Bur. J. Biochem. (1984), 138, p. 9-37. Exceptwhen otherwise stipulated, all the amino acids described are (L)-aminoacids.

The following examples illustrate the invention.

The various products and synthetic intermediates reported in theexamples were characterized by various analytical methods used under thefollowing conditions:

optical rotation (α): measured at 589 nm at 25° C.

Thin layer chromatography (TLC):

Merck 60F-254 silica gel plates eluents:

R_(f)(1) Ethyl acetate:n-butanol:acetic acid:water 1:1:1:1

R_(f)(2) Acetonitrile:chloroform:acetic acid:water 5:2:2:1

R_(f)(3) Acetonitrile:chloroform:acetic acid:water 7:4:4:2

HPLC chromatography:

5 μm Vydac C-18 column

Elution:

98% A+2% B to 25% A+75% B gradient over 49minutes (A=water containing0.1% trifluoroacetic acid; B=acetonitrile containing 0.1%tri-fluoroacetic acid)

Flow rate=2 ml/min

Detection: 220 nm UV

Nuclear magnetic resonance (NMR):

500 MHz Brüker AMX apparatus

Shift given in ppm

Appearances of the resonances:

m=multiplet,

s=singlet,

d=doublet,

t=triplet,

q=quartet,

quint=quintet,

o=octet.

EXAMPLE 1 Synthesis of N^(ε)- (N^(α)- tryptophanocarbonyl) lysine

5.1 g (25 mmol) of tryptophan, 1.34 g (5 mmol) ofN^(ε)-(phenyloxycarbonyl)lysine and 1.05 g (25 mmol) of LiOH.H₂O wereweighed into a 100 ml round-bottomed flask and then 40 ml of water wereintroduced into the round-bottomed flask. The latter was immersed in anoil bath maintained at 75° C. for 45 minutes, was then rapidly cooled toroom temperature under flowing water and then treated with 25 ml ofhydrochloric acid. The precipitate formed was filtered, after leavingovernight in a refrigerator.

HPLC analysis showed complete conversion of theN^(ε)-(phenyloxycarbonyl)lysine to 2 products having, under the analysisconditions, a retention time (t_(R)) of 12.23 and 13.95 minutes, with a13:1 ratio in the peak surface areas. The products were separated byinjecting the filtrate as is into a preparative C-18 HPLC column andthen lyophilized. 880 mg of N⁶⁸-N⁶⁰ -tryptophanocarbonyl)-lysine and 76mg of N⁶⁸ -(N^(ε)-(N⁶⁰ -tryptophanocarbonyl)-N⁶⁸ -lysinocarbonyl)lysinewere obtained. The physicochemical properties ofN⁶⁸-(N^(α)-tryptophanocar-bonyl)lysine are the following:

M.p.: 133° C.

α:+3.31(c=1, 1% acetic acid)

TLC: R_(f)(3)=0.34

NMR (H-1)in d₆-DMSO:

11.00 (1H,s), indole NH 7.50 (1H,d), indole H4 7.32 (1H,d), indole H77.09 (1H,s), indole H2 7.03 (1H,t), indole H6 6.94 (1H,t), indole HS6.28 (1H,broad t), Lys εNH 6.18 (1H,d), Trp αNH 4.36 (1H,m), Trp Hα 3.30(1H,m), Lys Hα 3.12 (1H,dd), Trp HβA 2.99 (1H,dd), Trp HβB 2.94 (2H,m),Lys Hε's 1.70 (1H,m), Lys HβA 1.60 (1H,m), Lys HβB 1.31 (4H,m), LysHγ's + Hδ's

EXAMPLE 2 Synthesis of N^(ε)-(methioninocarbonyl)lysine

N⁶⁸ -(Methioninocarbonyl) lysine was prepared from methionine andN⁶⁸-(phenyloxycarbonyl)lysine according to the same recipe as thatdescribed in Example 1. It has the following physicochemical properties:

M.p. : 148° C.

α:- 9.5(c=1, 1% acetic acid)

TLC : R_(f)(3)=0.27

HPLC : t_(R)=7.14 min

NMR (H-1) in d₆-DMSO:

6.43 (1H,broad d), Met NHα 6.33 (1H,broad t), Lys NHε 4.11 (1H,m), MetHα 3.35 (1H,m), Lys Hα 2.95 (2H, m), Lys Hε's 2.33 (2H,t), Met Hγ's 2.02(3H,s), Met CH₃ 1.88 (1H,m), Met HβA 1.77 (1H,m), Met HβD 1.72 (1H,m),Lys HβA 1.65 (1H,m), Lys HβB 1.33 (4H,m), Lys Hγ's + Hδ's

EXAMPLE 3 Synthesis of (D)-2-oxohexahydro-1.3-diazepinyl-4-carboxylicacid

7.7 ml (± 100 mmol) of 25% aqueous ammonia were added to a suspension of1.27 g (5 mmol) of (D) -N⁶⁷- (phenyloxycarbonyl)ornithine in 15 ml ofdimethoxyethane and 10 ml of water. The degree of conversion wasmonitored by TLC. Once the (D)-(phenyloxycarbonyl)ornithine haddisappeared, the reaction mixture was concentrated to dryness. Theresidue was triturated with 20 ml of 80% acetone, filtered and dried. Atthis stage, it was determined by NMR that the crude product obtained wasthe ammonium salt of (D)-2-oxohexahydro-1,3-diazepinyl-4-carboxylicacid, contaminated with approximately 5% of citrulline (Yield: 820 mg or92% as crude product). (D) -2-Oxohexahydro-1,3-diazepinyl-4-carboxylicacid was obtained, with a purity greater than 98%, by passing the crudeproduct as an aqueous solution through an ion exchange resin columm inthe H⁺ form and then lyophilizing.

M.p. : 130−150° C. (decomposition)

α:+14.6(c=1, water)

TLC : R_(f)(3): 0.70 no longer reacting with ninhydrin

R_(f)(3): 0.16 for citrulline

R_(f)(3): 0.54 for N⁶⁷- (phenyloxycarbonyl) ornithine

NMR (H), ref d₆-DMSO at 2.49:

6.20 (1H,broad s), NH1 5.55 (1H,broad s), NH3 3.75 (1H,m), H4 2.89(2H,m) H7 1.90 (1H,m) H5A 1.77 (1H,m) H5B 1.55 (2H,m), 6 H's NMR(C-13)ref d₆-DMSO at 39.50: 173.45 (COOH) 163.65 (C2) 54.43 (C4) 31.03 (C5)26.81 (C6)

EXAMPLE 4 Synthesis of (L)-2-oxohexahydropyrimidinyl-4-carboxylic acid

2 g (8.3 mmol) of (L)-N⁶⁵-(phenyloxycarbonyl)di-aminobutyric acid weredissolved in 10 ml of water and 5 ml of methanol. After addition of 3 ml(22 mmol) of triethylamine, the solution was heated under gentle refluxuntil the starting material had completely disappeared (monitoring byTLC). The solution was concentrated to dryness and then suspended in 50ml of dichloro-methane. The product, then in the triethylamine(L)-2-oxohexahydropyrimidinyl-4-carboxylate form, was displaced byaddition of 1.8 ml of trifluoroacetic acid. As triethylaminetrifluoroacetate is very soluble,(L)-2-oxohexahydropyrimidinyl-4-carboxylic acid selectivelyprecipitates. It was recovered by filtration, washed withdichloromethane and then dried.

Yield : 95%

α:+20.1 (c=1, water)

TLC : R_(f)(2)=0.55

NMR(¹H) ref D₂O at 4.80:

4.27 (1H,t), Hα 3.35 (1H,d of t), HγA 3.22 (1H,o), HγB 2.13 to 2.18(2H,m), HβA + B

EXAMPLE 5 Synthesis of(2-oxohexahydro-1,3-diazepinyl-4-carbonyl)-His-Pro-NH₂

1 g (1.40 mol) of N⁶⁷-(phenyloxycarbonyl)Orn-His-Pro-NH₂bis(trifluoroacetate) was dissolved in 10 ml of methanol containing 0.75ml (5.4 mmol) of triethylamine. The solution was brought to gentlereflux at a temperature of approximately 65° C. until the startingmaterial had disappeared (monitoring by TLC). The solution wasconcentrated to dryness and triturated with 20 ml of dichloromethane.After filtration, the crude product collected (0.52 g) was purified byC-4 reverse phase preparative chromatography. The analytical sampleisolated in the acetate salt form has the following physicochemicalproperties:

α=−8.1(c=1, 1% acetic acid)

M.p.: 105° C.

TLC R_(f)(1)=0.42

NMR (¹ H, D₂O ): Some resonances are split due to the cis/transisomerism at the His-Pro bond. The results for the major form (±85%) aretaken up below:

8.56 (1H,s), imidazole H2 7.34 (1H,s), imidazole H5 5.08 (1H,dd), His Hα4.46 (1H,dd), Pro Hα 4.07 (1H,dd), Odc Hα 3.61 (1H,m), Pro HδA 3.65(1H,m), Pro HδB 3.30 (1H,dd), His HβA 3.19 (1H,dd), His HβB 3.08 to 3.02(2H,m), Odc HδA + B 2.36 (1H,m), Pro HβA 2.15 to 1.95 (5H + acetate CH₃)1.74 (1H,m) Odc HγA 1.51 (1H,m), Odc HγB

EXAMPLE 6 Synthesis of (2-oxohexahydropyrimidinyl-4-carbonyl)His-Pro-NH₂

432 mg (3 mmol) of (L)-2-oxohexahydropyrimidine-4-carboxylic acid weredissolved in 10 ml of N-methylpyrrolidone containing 0.33 ml (3 mmol) ofN-methylmorpholine. 0.39 ml of isobutyl chloroformate were added to thesolution cooled to −10° C. After reacting for 5 minutes at −10° C., asolution of 5 ml of N -methyl-pyrrolidone containing 1.25 g (3 mmol) ofHis-Pro-NH₂·2HBr and 0.90 ml of triethylamine (6.5 mmol) was added.After maturing for a time of 30 minutes at room temperature, thereaction mixture was added dropwise to 50 ml of ethyl ether. Theprecipitate obtained was filtered, then washed twice with 20 ml ofdichloromethane and dried, giving 1.3 g of product. It was purified bypassing through a column of silica gel, the same mobile phase being usedas in TLC.

Analytical data:

α=−23.8(c=1, acetic acid)

M.p.=140° C.

TLC: R_(f)(1)=0.33

NMR(¹H) in D₂O. Some resonances are split due to the cis/trans isomerismat the His-Pro bond. the results for the major form (±85%) are taken upbelow:

8.16 (1H,s), imidazole H2 7.21 (1H,s), imidazole H5 5.04 (1H,dd), His Hα4.48 (1H,dd), Pro Hα 4.17 (1H,broad s), Opc Hα 3.88 (1H,m), Pro HδA 3.68(1H,m), Pro HδB 3.30 (2H,broad d), His HβA + Opc HγA 3.14 (1H,dd), HisHβB 2.78 (1H,m), Opc HγB 2.37 (1H,m) Pro HβA 2.20 to 2.00, Pro HβB +Hγ's/Opc Hβ's

What is claimed:
 1. Cyclic ureins of general formula

in which A represents a bivalent group consisting of a linear carbonchain formed from 3 carbon atoms, which chain is optionally substitutedby one or a number of groups chosen from C₁-C₃ alkyl groups andfunctional groups comprising at least one oxygen or sulphur atom.
 2. Theurein of claim 1, in which the functional group comprises at least oneoxygen atom.
 3. The urein of claim 1, in which the functional groupcomprises at least one oxygen atom and is selected from the groupconsisting of carboxyl, acyl, hydroxyl and alkoxy.
 4. The urein of claim1, in which the functional group comprises at least one sulphur atom. 5.The urein of claim 1, in which the functional group comprises at leastone sulphur atom and is a mercapto group.
 6. The urein of claim 1, inwhich A represents a trimethylene group —(CH₂)₃—.
 7. Peptides of generalformula

in which A is a bivalent group consisting of a linear carbon chainformed from 3 carbon atoms, which, chain is optionally substituted byone or a number of groups selected from the group consisting of C₁-C₃alkyl groups and functional groups comprising at least one oxygen orsulphur atom.
 8. The urein of claim 7, in which the functional groupcomprises at least one oxygen atom.
 9. The urein of claim 7, in whichthe functional group comprises at least one oxygen atom and is selectedfrom the group consisting of carboxyl, acyl, hydroxyl and alkoxy. 10.The urein of claim 7, in which the functional group comprises at leastone sulphur atom.
 11. The urein of claim 7, in which the functionalgroup comprises at least one sulphur atom and is a mercapto group.